Today, there are many different classes of antibiotics available to medical practitioners. However, many of the bacteria that these antibiotics are designed to treat are quickly developing resistance to drugs in all classes. Unfortunately the large pharmaceutical companies have limited there research in finding new antibiotics. Several bacteria have become particularly prominent in recent years and have garnered substantial media attention, especially methicillin-resistant Staphylococcus aureus (“MRSA”) and Streptococcus pyogenes. MRSA infections on the skin and in the airways are common in hospital settings and the broad spectrum resistance of the bacteria to almost all classes of antibiotics (e.g. methicillin, fusidic acid and mupirocin) make it particularly difficult to combat. MRSA infections in patients who have not recently been in hospital (so called community acquired MRSA infections) are becoming increasingly frequent.
The problem of antibiotic resistance is an increasing problem, but a truly comprehensive solution to the problem has yet to emerge. A major problem in the battle against antibiotic resistance is the lack of novel antibiotics to replace those that no longer effectively treat organisms due to resistance development. New treatments are urgently needed to address this issue of drug resistance.
Fusidic acid is an antibiotic derived from Fusidium coccineum that has been used for over 35 years to treat infections with Staphylococcus aureus. In particular, fusidic acid is prescribed for skin infections caused by Staphylococcus aureus. Such infections include impetigo, angular cheilitis (an infection around the mouth), and infected dermatitis. It works by stopping the growth of the bacteria causing the infection.
Fusidic acid resistance in S. aureus can be readily selected for by in vitro exposure to the antibiotic, leading to the recommendation that for systemic therapy fusidic acid should only be given in combination with another agent. More controversial is the use of topical fusidic acid in the treatment of cutaneous and soft tissue infections.
Increasing fusidic acid resistance in Staphylococcus aureus might be important for three reasons. First, it might mean that systemic fusidic acid can no longer be used in situations where it is clinically indicated. Second, failure of topical treatment may occur, especially in primary care settings where treatment is often empiric. Third, resistance to fusidic acid might be linked to other antibiotic resistances, therefore favoring spread of multiply antibiotic resistant Staphylococcus aureus such as MRSA (methicillin-resistant S aureus).
Mupirocin is a topical antibiotic used to treat superficial skin infections and to control the spread of methicillin-resistant Staphylococcus aureus (MRSA). Mupirocin resistance was observed shortly after it became available. Prevalence of mupirocin resistance among MRSA isolates has been described mostly in hospitalized adult and elderly patients with wide variability, ranging from 0 to 65% of isolates. Rates of resistance have been shown to correlate with increased use in closed inpatient settings. Very restrictive mupirocin prescriptions for local treatment are now recommended.
Impetigo is a highly contagious bacterial infection of the superficial layers of the epidermis. Impetigo is one of the most common skin diseases among children, accounting for about 10% of skin diseases treated in U.S. paediatric clinics. The bacteria typically considered to be responsible are Staphylococcus aureus and Streptococcus pyogenes, and often a combination of the two. Impetigo is usually transmitted by direct contact but fomites also play an important role. Methicillin-resistant Staphylococcus aureus (MRSA) is being found with increasing frequency as a causative bacteria of impetigo. Impetigo has three common clinical varieties: impetigo contagiosa (common impetigo), bullous impetigo, and ecthyma. Features of all three types of impetigo, however, may coexist in any individual patient.
A number of topical compositions containing pharmaceutically active ingredients are known for the treatment of impetigo. Topical mupirocin 2% (Bactroban ointment and cream) is a treatment option, as arc older treatments, such as topical gentian violet and vioform. For many patients, mupirocin is a viable treatment option for MRSA, however, resistance of bacteria to mupirocin has been widely reported.
Topical fusidic acid 2% (Fucidin cream) is used for treatment of impetigo, and is thought to be equally as effective as mupirocin. However, the utility of fusidic acid for treatment of impetigo is limited by the problem of resistance development, as discussed above.
Fusidic acid-resistant Staphylococcus aureus (FRSA) has been identified as a causative bacteria in outbreaks of impetigo and its emergence has been associated with increased use of topical fusidic acid. Accordingly, utility of fusidic acid as first-line agent for the treatment of impetigo is questionable due to current resistance levels in the target bacteria. Retapamulin 1% (Altabax ointment), recently approved by the FDA, is a drug in the new class of pleuromutilin antibiotics for the topical treatment of impetigo due to Staphylococcus aureus (methicillin-susceptible only) or Streptococcus pyogene. 
A wound is an injury to the body (as from violence, accident, or surgery) that typically involves laceration or breaking of a membrane (as the skin) and usually damage to underlying tissues (Merriam Webster Dictionary). Burns are injuries to tissues caused by heat, friction, electricity, radiation, or chemicals. Wounds and burns are often colonized by microbiologic pathogens, including Gram-positive bacteria, such as Staphylococcus aureus and/or Streptococcus pyogenes; and Gram-negative bacteria, e.g. Pseudomonas aeruginosa. 
Despite the very common occurrence of skin infections, only a limited number of topical antibiotics are approved for the treatment of wounds and particularly infected wounds. Mupirocin (Bactroban) is an antibiotic, developed by GSK. Emerging resistance to mupirocin is becoming a concern. In coagulase-negative staphylococci isolates, mupirocin resistance rates are higher, ranging from 12.7% in Europe to 38.8% in the United States. Retapamulin (Altabax, GSK) is another topical antibiotic used for wound treatment. Fucidin (LEO Pharma) is also effective in primary and secondary skin infections caused by sensitive strains of Staphylococcus aureus, Streptococcus species and Corynebacterium minutissimum. 
Bacterial infections are a leading cause of death worldwide, and bacterial resistance is greatly reducing available treatment options. There is therefore a need for new antibiotics, for which development of resistance is not widespread in the target bacteria, for the prevention and treatment of topical infections caused or contributed to Gram-positive bacteria such as Staphylococcus aureus and Streptococcus pyogenes is strongly warranted.
The halogenated salicylanilides are a series of compounds generally used as anthelmintic agents. One such compound is niclosamide (5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenz-amide; also known as 2′,5-dichloro-4′-nitrosalicylanilide, 2-hydroxy-5-chloro-N-(2-chloro-4-nitrophenyl)-benzamide, 5-chloro-2′-chloro-4′-nitrosalicylanilide or 5-chloro-N-(2-chloro-4-nitrophenyl)-salicyl amide):

Acute toxicity of niclosamide:                LD50, mice, p.o., >5000 mg/kg        LD50, rats, p.o., 5000 mg/kg        LD50, rats, dermal, 2000 mg/kg        LD50, rabbits, p.o., 5000 mg/kg        LD50, cats, p.o., >1000 mg/kg        
Niclosamide is a known taenicide (=tapeworm killer) effective against several parasitic tapeworms of livestock and pets (e.g. Taenia spp, Moniezia spp) and also against rumen flukes (Paramphistomum spp) and blood flukes (Schistosoma spp). This is in contrast with most other salicylanilides, which generally exhibit activity as flukicides but not as taenicides.
Niclosamide is currently used in humans as an anthelmintic drug to treat intestinal infections and displays overall low toxicity, it is poorly soluble in water, shows low intestinal absorption, and once in the bloodstream, it is quickly cleared via the urinary tract or by enzymatic metabolism in the liver. Therapeutically it is useful against cestoda in humans.
Niclosamide has also been shown to prevent the penetration of Schistosoma mansoni through the human skin. As well as used as an anticancer drug, pesticide and as an anti-trypanosoma drug. Virtually all applications and proposed applications of niclosamide target eukaryotic organisms.
Niclosamide has also been shown to inhibit viral replication in human cells. However, the mechanism is believed to be through targeting human host cells to provide conditions that prevent the viral life rather than specifically targeting the virus. Accordingly, the viral application of niclosamide result from its ability to target an eukaryotic process.
Niclosamide is commercially available in a number of formulations including, but not limited to Bayer73®, Bayer2353®, Bayer25648®, Bayluscid®, Baylucide®, Cestocid®, Clonitralid, Dichlosale®, Fenasal®, HL 2447®, Iomesan®, Iomezan®, Manosil®, Nasemo®, Niclosamid®, Phenasal®, Tredemine®, Sulqui®, Vermitid®, Vermitin® and Yomesan®.
Other halogenated salicylanilide compounds are                Closantel, (N-[5-chloro-4-[(4-chlorophenyl)cyanomethyl]-2-methylphenyl]-2-hydroxy-3,5-diiodobenzamide) is used as a veterinary anthelmintic:        

Acute toxicity of closantel:                LD50, rats, p.o., 262-342 mg/kg (depending on the study), median 302 mg/kg        LD50, rats, s.c., 67 mg/kg        LD50, mice, p.o., 331 mg/kg        LD50, mice, i.m., 57 mg/kg        Rafoxanide (3′-chloro-4′-(p-chlorophenoxy)-3,5-diiodosalicylanilide) is known for veterinary use as a fasciolicide and anthelmintic.        

Acute toxicity of rafoxanide:                LD50, rats, p.o., 980->2000 mg/kg (depending on the study), median>1490 mg/kg        LD50, mice, p.o., 232-300 mg/kg (depending on the study), median 266 mg/kg        LD50, rabbits, p.o., 3200 mg/kg        Oxyclozanide (3,3′,5,5′,6-pentachloro-2′-hydroxysalicylanilide), is known for veterinary use as an anthelmintic, primarily against trematodes.        
                LD50, rats, p.o., 980-3519 mg/kg (depending on the study), median 2250 mg/kg        LD50, mice, p.o., 300 mg/kg        LD50, rabbits, p.o., 3200 mg/kg        Low safety margin after oral administration        
The molecular mode of action of salicylanilides, including niclosamide, is not completely elucidated. They all are uncouplers of the oxidative phosphorylation in the cell mitochondria, which disturbs the production of ATP. This impairs the parasites motility and probably other processes as well. Niclosamide acts on the tapeworms also through inhibition of glucose absorption
Niclosamide has been proposed as a possible systemic treatment for chronic lung infections caused by the proteobacterium Pseudo-monas aeruginosa and the actinobacterium Mycoplasmum tuberculosis. Niclosamide has been shown to reduce the quorum sensing response as well as the production of quorum sensing metabolites in P. aeruginosa. Since quorum sensing is considered an important process for the pathogenicity during chronic lung infections caused by this bacterium, it led to proposal that niclosamide could be used as an adjuvant therapy for these infections. Niclosamide does not affect the growth of P. aeruginosa and accordingly does not have any direct antibacterial activity. The concentration required for optimal activity was 20 μM, however, some inhibition was detected at 1 μM. (F. Imperi et al., Antimicrobial, Agents and Chemotherapy, 557(2), 996-1005 (2013)).
Ghazi et al. (Zentralbl. Mikrobiol. 141 (1986), 225-232) tested the antibacterial effect and toxicity of synthesized salicylanilide derivatives against Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa and Staphylococcus aureus but nothing is mentioned about the rate of resistance development.
J. Vinsova et al. describe the antibacterial activity of salicylanilides (Molecules, vol. 12, no. 1, pp. 1-12, 2007; Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 2, pp. 348-351, 2009; European Journal of Medicinal Chemistry, vol. 45, no. 12, pp. 6106-6113, 2010), but nowhere mentioned the problem with resistance development.
M. J. Macielag et al. tested the antibacterial activity of closantel and related derivatives against the drug-resistant organisms, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF) (J. Med. Chem., 41(16), 2939-45 (1998)) but nowhere mentioned the problem with resistance development.
D. J. Hlasta et al found that closantel had antibacterial activity against drug resistant S. aureus and E. faecium (Bioorg. Med. Chem. Letters, 8(14), 1923-28 (1998)), but nowhere mentioned the problem with resistance development.
R. Rajamuthiah et al. identified closantel as a hit in a high throughput liquid screening assay and found anti-staphylococcal activity of closantel against vancomycin-resistant S. aureus isolates and other Gram-positive bacteria. There is no mention of the problem of resistance development (PloS One, 2014, 9(2): e89189).
WO 2008/155535 describes the use of halogenated salicylanilides for the treatment of acne, wherein propionibacteria is the bacteria causing the acne. There is no mention of the problem with resistance development.